It is estimated that the annual incidence of spinal cord injury (SCI), not including persons who die at the scene of the accident, is approximately 11,000 cases per year. The number of patients currently affected by SCI in the United States has been estimated at 250-300,000. Currently patients with SCI face a life-long sentence of extreme morbidity. Hepatocyte growth factor (HGF), also known as Scatter factor (SF), has documented scattering, proliferating, and protective effects on neurons in the brain, spinal cord, and in peripheral nerves, and has significant potential as a novel therapeutic agent for the treatment of brain and SCI. Administration of an HGF/SF-like compound holds promise as a new approach to the clinical management of SCI. However, treatment modalities that employ gene- or protein-based formulations are characteristically expensive and difficult to administer. Therefore, therapeutic approaches that employ small molecule mimetics of natural growth and protective factors may be powerful alternatives to such therapies. The primary focus of research at Angion Biomedica is the development of small molecules that regulate HGF/SF/Met signaling to therapeutic advantage. To this end, we have identified a small molecule, Refanalin, that recapitulates the biologic activity of HGF/SF by activating the HGF/SF receptor, Met. Our working hypothesis is that Refanalin acts as a neuroprotectant while promoting cell proliferation, axonal growth, and functional recovery in the setting of SCI. As delineated in our Progress Report, administration of this small molecule mimetic of HGF/SF represents a highly innovative approach for the treatment of SCI, with significant clinical potential. In vitro, Refanalin activates the same intracellular signaling cascades as HGF/SF, scatters renal cells, induces endothelial, epithelial and Schwann cell proliferation, and protects against apoptotic and necrotic cell death. In an experimental model of spinal cord ischemia, Refanalin improves neurological recovery and preserves neuronal and grey matter integrity. Importantly, in a well-described and clinically relevant model of SCI, Refanalin improves neurobehavioral score, attenuates neuronal cell death and augments neuronal regeneration. A comprehensive and good laboratory practice adherent set of regulatory studies indicates that acute systemic administration of Refanalin is safe and well- tolerated. Long-term (3-month) safety studies of Refanalin undertaken by the National Institutes of Health NIH Rapid Access to Interventional Development program are underway and preliminary results are extremely encouraging. This translational research Phase II application is designed to explore fully the therapeutic potential of Refanalin in SCI. Dose-response, treatment time window and dosing schedule studies for Refanalin will be followed by determination of Refanalin efficacy in clinically relevant models of SCI. Successful completion of the proposed research will enable submission of an Investigational New Drug Application to Food and Drug Administration FDA for clinical studies with Refanalin. The primary focus of this proposal is the development of small molecules that regulate SF/HGF/Met signaling to therapeutic advantage. Our lead HGF/SF mimetic, Refanalin recapitulates the biologic activity of HGF/SF by activating the HGF/SF receptor, and represents a highly innovative approach to the treatment of spinal cord injures, with significant clinical potential. [unreadable] [unreadable] [unreadable]